Molecular and cellular mechanisms in neuroinflammatory disease

Summary

Molecular genetic and functional genomic approaches will be used to determine how immune hormones termed cytokines and chemokines communicate with cells in the central nervous system to cause inflammation and injury.

Supervisor(s)

Professor Iain Campbell

Research Location

School of Molecular Bioscience

Program Type

PHD

Synopsis

Background:Inflammation occurs in response to injury or infection of the central nervous system (CNS). There is increasing evidence that this inflammatory process may cause significant damage to neural tissues leading to neurological impairment and disease. Cytokines (including chemokines) are biological response modifiers and primary regulators of inflammation. Cytokines are known to alter the activity of cells by binding to specific cell surface receptors that trigger signal transduction pathways resulting in altered gene expression. Evidence from previous work by the Campbell lab has shown that cytokines can act directly to cause neurological disease.Overall Goal:Currently little is known as to how cytokines function in the CNS to cause inflammation and disease. Addressing this gap in our knowledge is a major goal of this research program. The overall objective is to elucidate the precise signal transduction mechanisms employed by different cytokines to alter the gene expression program and phenotype of cells within the CNS.Research Approach:Cytokine signal transduction mechanisms will be studied in mouse models that have been engineered for CNS-targeted production of different cytokines. The signal transduction pathways activated by these cytokines will be identified and subsequently manipulated using molecular genetic approaches. The consequences of altered signal transduction on the gene transcriptional profiles of the brain will be established and linked to specific molecular and cellular alterations.Outcome and Significance:The results of this research will clarify the mechanisms of cytokine signal transduction and actions in the living brain. The knowledge gained from this research will be essential for the future development of better approaches for combating autoimmune and infectious diseases of the CNS. They also have broader implications for understanding the mechanisms of action of cytokines in other tissues and diseases.

Additional Information

Current Ph.D. projects:

  1. The CNS pathobiology of the IFN-inducible non-ELR chemokines. The goals of this project are to determine the contribution of the chemokines belonging to the CXCR3 chemokine family to immunoinflammatory diseases within the CNS and to define the regulatory mechanisms that control the production of these chemokines within the CNS.
  2. Signal Transduction Mechanisms in Interleukin-6-Induced Inflammation and Injury in the Central Nervous System. The goal of this project is to define the relative contribution of the gp130 coupled JAK/STAT and SHP2 phosphatase pathways in mediating the actions of IL-6 in the CNS.
Techniques used in the projects will include:Genetic engineering-transgenesis, targeted gene mutation, gene transduction/transfection; gene expression analysis-microarray, chromatin immunoprecipitation assay, RNase protection assay, in situ hybridization histochemistry; Proteomic analysis-antibody arrays, immunohistochemistry/cytochemistry, immunoblotting, fluorescence activated cell sorting analysis; Tissue culture-isolation and culture of primary brain cells. Image analysis-light and fluorescence microscopy.Possible research areas for Ph.D. projects: A number of research projects are available that take advantage of the various CNS-cytokine transgenic models available in the Campbell laboratory. These are evolving continuously as advances are made in the research program but all projects will fall within the general themes outlined above. Interested students are advised to contact the project supervisor to discuss potential Ph.D. projects.

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Keywords

multiple sclerosis, Neuroimmunology, Autoimmune neurological disease e.g. multiple sclerosis, Neurovirology, Viral and bacterial encephalitis, Cytokine immunobiology, Neurodegeneration, Disease pathogenesis, Transgenics, Animal models of disease, Brain & nervous system disorders, Infectious diseases, Cell biology, Infection & immunity, Neuroscience & psychology

Opportunity ID

The opportunity ID for this research opportunity is: 27